This proposal is a two-part study aimed at developing radiopharmaceuticals that probe the actions of specific brain neurotransmitters. Significant changes in binding of the neurotransmitter glutamate occur in the brains of patients with senile dementia of the Alzheimer's type and Huntington's Disease. The first major goal of this proposal is to develop a positron- emitting radiotracer that will permit regional quantitation of glutamate receptor density (NMDA subset) in the human brain. Non-radioactive analogs of the dissociative anesthetic phencyclidine (PCP) and the anti-convulsant MK-801 that are clearly amenable to positron labeling will be synthesized and screened in vivo for pharmacological (PCP-like) potency using the mouse platform test. Relative binding affinities (IC-50 values) of these compounds for the NMDA-linked ion channel will be determined by in vitro quantitative autoradiography using a competitive H-3-ligand assay. The most promising agents will be H-3-labeled and their in vivo metabolism and temporal pattern of whole brain uptake determined in rats; regional brain distribution and receptor-site specificity will be determined by H-3- autoradiography. The best agent(s) will be labeled with F-18 or C-11 and its regional distribution in monkey brain determined by positron emission tomography (PET) under normal and drug challenge conditions. Dosimetric and toxicity studies will be conducted in animals in pursuit of human use approval for this agent for studying Alzheimer's and presymptomatic Huntington's Disease and convulsive disorders. Preliminary pharmacological screening of 3-amino-4-fluoro-PCP shows this compound to be as pharmacologically potent as PCP. Initial experiments indicate that this agent can be labeled with F-18 in high specific activity. The second major goal of this proposal is to develop a positron- emitting radiotracer that will map alpha-2 receptors in the human brain. The two potent alpha 2 antagonists, 2-methoxyidazoxan and the structurally related 1,4-benzodioxan RS-21361, will be H- 3-labeled and their metabolism, pharmacokinetics and regional brain distribution determined in rats. A quantitative tracer kinetic model will be developed to derive kinetic parameters from the regional brain distribution of these radiotracer(s). The superior agent will be C-11-labeled and its regional distrubition in the monkey brain assessed by PET. Human use approval will be sought for study of alpha 2 receptor alteration in depression.